An Update on Immunopathogenesis, Diagnosis, and Treatment of Multiple Sclerosis Neeta Garg1 & Thomas W

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An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis Neeta Garg1 & Thomas W. Smith2 1Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 2Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

Keywords Abstract Demyelination, diagnosis, etiology, immunomodulator, multiple sclerosis, Background: Multiple sclerosis is an acquired demyelinating disease of the cen- pathogenesis, treatment tral nervous system. It is the second most common cause of disability in adults in United States after head trauma. Discussion: The etiology of MS is probably Correspondence multifactorial, related to genetic, environmental, and several other factors. The Neeta Garg, Department of Neurology, pathogenesis is not fully understood but is believed to involve T-cell-mediated University of Massachusetts Medical School, inflammation directed against myelin and other related proteins with a possible 55 Lake Ave North, Worcester, MA 01655. role for B cells. The McDonald criteria have been proposed and revised over Tel: +508 334 2527; Fax: +774 442 9122; E-mail: [email protected] and the years to guide the diagnosis of MS and are based on clinical presentation Thomas W. Smith, Department of and magnetic resonance imaging (MRI) of the brain and spinal cord to estab- Pathology, University of Massachusetts lish dissemination in time and space. The treatment of MS includes disease Medical School, 55 Lake Ave North, modification with immunomodulator drugs and symptom management to Worcester, MA 01655. Tel: +508 856 address the specific symptoms such as fatigue, spasticity, and pain. Conclusion: 2331; Fax: +508-793-6110; E-mail: Thomas. An update on etiology, pathogenesis, diagnosis, and immunomodulatory treat- [email protected] ment of MS is presented. Funding Information No funding information provided.

Received: 9 January 2015; Revised: 13 April 2015; Accepted: 4 May 2015

Brain and Behavior, 2015; 5(9), e00362, doi: 10.1002/brb3.362

Introduction triggering an aberrant autoimmune attack resulting in damage to myelin and axons (Bruck and Stadelmann 2005). Multiple sclerosis is an autoimmune inflammatory disorder The course of MS can be variable with a significant propor- of CNS of unknown etiology, characterized by demyelination of patients experiencing some progression following the tion and variable degrees of axonal loss. The disease affects initial relapsing remitting phase leading to significant dis- mostly young women (between ages 20 and 40 years) and is ability (Weinshenker et al. 1989; Lublin and Reingold 1996). one of leading causes of disability in young adults in United Much progress has been made in the past two decades in States (Orton et al. 2006; Kister et al. 2013). Its prevalence treating MS with the advent of effective immunomodulatory in the United States is about 400,000 and over two million therapies which can potentially slow down the progression people are affected worldwide with an expected increase in and alter the disease course. the number of cases in future (Weinshenker 1996; Mayr et al. 2003). The disease appears to be more common in Etiology northern hemisphere and there is some genetic susceptibility as well in individuals of Scandinavian or northern European The etiology of MS remains unknown; however, it is ancestry (Williams et al. 1995; Compston and Coles 2008). believed to be caused by immune dysregulation triggered The etiology although unknown presumably involves inter- by genetic and environmental factors (Ascherio and action between genetic, environmental, and other factors Munger 2007a,b). Although MS is not an inherited

ª 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Brain and Behavior, doi: 10.1002/brb3.362 (1 of 13) This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. An update on Multiple Sclerosis N. Garg & T. W. Smith disease, there is a strong genetic component to its etiology other risk factors, smoking appears to influence the MS as evidenced by clustering of MS cases within families. susceptibility in conjunction with the genetic and other The risk of MS among first-degree relatives of MS environmental factors. patients is 10–50 times higher than the general population There is no specific diet associated with increased risk (absolute risk 2–5%); the concordance rate in monzygotic of MS. The role of dietary factors appears to be complex twins is about one-third (Weinshenker 1996; Kantarci and related to the influence of multiple dietary compo- 2008). Linkage analysis studies have revealed several gene nents including vitamin A and D, salt, omega-3-unsatu- loci as risk factors, with the major histocompatibility rated fatty acid, and polyphenol on immune regulation. complex (MHC) HLA DR15/DQ6 allele being the strong- Some recent reports have suggested that salt modulates est one (Barcellos et al. 2003; Sawcer et al. 2011). More the differentiation of human and mouse Th17 cells recently, alleles of interleukin-2 receptor alpha gene (Kleinewietfeld et al. 2013; Wu et al. 2013). A more (IL2RA) and interleukin-7 receptor alpha gene (IL7RA) aggressive course of experimental autoimmune encephalo- have also been identified as inheritable risk factors (Hafler myelitis (EAE) was observed in mice fed a high sodium et al. 2007; Sawcer et al. 2011). However, most of the diet. In a small observational study, higher sodium intake genetic factors underlying susceptibility still remain to be was associated with increased clinical and radiological dis- defined. Furthermore, genetic susceptibility does not fully ease activity in patients with MS (Farez et al. 2015). explain the changes in MS risk that occur with migration The potential risk factors for MS are listed in Table 1. suggesting a likely role for environmental factors. Among environmental factors, Epstein-Barr virus Immunopathogenes (EBV) infection and vitamin D deficiency have been extensively studied and strongly linked to MS risk (Asche- The pathogenesis of MS involves immune attack against rio and Munger 2007a,b) MS is prevalent in geographic CNS antigens mediated through activated CD4+ myelin- areas farther away from the equator (Simpson et al. reactive T cells with a possible contribution by B cells. 2011). Low vitamin D levels from reduced sun exposure Much of our understanding of immunopathogenesis of may be a factor contributing to increased susceptibility to MS is derived from the study of experimental autoim- MS in these regions (Ascherio and Munger 2007b; Corre- mune encephalomyelitis (EAE), an animal model of CNS ale et al. 2009; Ascherio et al. 2010). Studies have sug- inflammatory demyelination that can be induced by gested that higher levels of vitamin D have a possible peripheral immunization with myelin protein compo- protective role in certain susceptible patient populations nents. EAE shares many of the histologic features of MS (Munger et al. 2004, 2006). The risk of developing MS is including active demyelination, oligodendrocyte and axo- approximately 15-fold higher among individuals with a nal loss, all of which are presumably mediated by myelin history of EBV infection in childhood and about 30-fold specific T cells (Yong 2004; Gold et al. 2006). The immu- higher among those infected with EBV in adolescence or nopathogenesis of MS is thought to involve a breach of later in life (Ascherio 2013). However, the difference in self-tolerance toward myelin and other CNS antigens the risk of MS among migrants from high to low MS resulting in persistent peripheral activation of autoreactive prevalence areas suggests that other infectious or nonin- T cells (Hafler et al. 2005; Selter and Hemmer 2013). In a fectious factors in addition to EBV may be involved genetically susceptible individual, this loss of self-tolerance (Ascherio and Munger 2007a,b). The “hygiene hypothe- may be triggered by an environmental antigen, presum- sis,” supported by many epidemiological observations, ably an infectious agent such as a virus. The infection suggests that improved sanitation and reduced childhood could cause bystander activation of T cells or result in infections in developed countries may account for the increased rates of autoimmune diseases (T-helper 1 mediated) and allergy (T-helper 2 mediated) (Conradi et al. Table 1. Potential risk factors for multiple sclerosis. 2011). However, this hypothesis does not explain the Female gender higher MS prevalence in rural compared to urban areas Caucasian race (with expected improved sanitation) reported in some Genetic studies (Sotgiu et al. 2003). HLA DR15/DQ6, IL2RA and IL7RA alleles Cigarette smoking has also been proposed at a potential Infections – environmental risk factor with several studies reporting Epstein Barr virus (EBV) infection Temperate climate an association between smoking and MS risk and disease Low vitamin D level activity (Wingerchuk 2012). The odds ratio for develop- Lack of sunlight exposure ing MS is approximately 1.5 for smokers compared with Cigarette smoking nonsmokers (Wingerchuk 2012; Fragoso 2014). As with

Brain and Behavior, doi: 10.1002/brb3.362 (2 of 13) ª 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. N. Garg & T. W. Smith An update on Multiple Sclerosis

+ release of autoantigens due to cellular damage, which can CD4 T-helper 1 (TH1) cells which release proinﬂamma- then lead to activation of T cells by cross reactivity tory cytokines such as interferon-gamma, interleukin-2 between an endogenous protein (e.g., myelin basic pro- (IL-2), and tumor necrosis factor-a (TNF-a) are the key tein) and the pathogenic exogenous protein (viral or bac- players in mediating inﬂammation in MS with some role + terial antigen), a process known as molecular mimicry for the novel CD4 T-helper-17 (TH17) cell subset which (Fujinami and Oldstone 1985; Wucherpfennig and secretes IL-17 (O’Connor et al. 2001; Selter and Hemmer + Strominger 1995; Aichele et al. 1996; Gran et al. 1999; 2013). The CD4 T-helper 2 (TH2) cells, which secret in- O’Connor et al. 2001). terleukins 4, 5, and 10 are believed to have a counter reg-

As depicted in Figure 1, once activated in the periph- ulatory role limiting the TH1-cell-mediated injury ery, myelin-reactive T cells are able to migrate across the (Tzartos et al. 2008). The TH1/TH2 paradigm is more blood–brain barrier (BBB). The transmigration process apparent in EAE; in MS, indirect evidence exists for a involves interaction between very late antigen-4 (VLA-4) predominant role of Th1 cells based on the success of present on T lymphocytes and the vascular cell adhesion therapies that shift the cytokine profile away from Th1 molecule-1 (VCAM-1) expressed on capillary endothelial toward Th2. CD8+ T cells are believed to be involved as cells; this process is facilitated by expression and upregu- well and can induce axonal pathology by direct injury to lation of various adhesion molecules, chemokines, and MHC I/antigen expressing cells such as neurons and oli- matrix metalloproteinases (MMPs) (Yong 2004; Gold and godendrocytes (Batoulis et al. 2010). The contribution of Wolinsky 2011). After entering the CNS, the autoreactive B cells to MS pathogenesis (possibly through autoanti- peripherally activated T cells can be reactivated upon body secretion and antigen presentation to T cells) has encountering the autoantigenic peptides within the brain recently been recognized and is supported by observed parenchyma in the context of MHC class II molecules pathologic heterogeneity of MS lesions, the presence of expressed by local antigen presenting cells (dendritic cells, meningeal inflammation and B-cell follicle-like structures macrophages, and B cells) triggering an inflammatory cas- adjacent to subpial cortical lesions, and the success of cade leading to release of cytokines and chemokines, B-cell-based immunotherapies (O’Connor et al. 2001; recruitment of additional inflammatory cells including T Batoulis et al. 2010; Naismith et al. 2010). cells, monocytes, and B cells and persistent activation of Although demyelination is the hallmark of MS pathol- microglia and macrophages resulting in myelin damage ogy, early axonal injury and axonal loss also occur and (Hemmer et al. 2002; Frohman et al. 2006; Inglese 2006). may drive disability progression (Trapp et al. 1998). The The local inflammation and demyelination results in exact mechanism(s) of both myelin and axonal injury are exposure of sequestered myelin autoantigens providing an not completely understood, but are likely to include both additional target for self-reactive T cells, a phenomenon direct injury to myelin and oligodendrocytes, and axons called “epitope spreading” (Miller et al. 1997). Activation by CD4+ and CD8+ T lymphocytes, activated microglia/ of resident CNS glial cells (such as microglia) results in macrophages, and/or antibody and complement as well as persistent inflammation even in absence of further infil- the indirect effects of proinflammatory cytokines such as tration of exogenous inflammatory cells (O’Connor et al. IL-1beta, TNF-a, nitric oxide, and MMPs (Lucchinetti 2001). The evidence based on animal studies suggests that et al. 2000; Hemmer et al. 2002; Gold and Wolinsky

Figure 1. Immunopathogenic mechanisms in MS and proposed targets of different disease modifying therapies.

ª 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Brain and Behavior, doi: 10.1002/brb3.362 (3 of 13) An update on Multiple Sclerosis N. Garg & T. W. Smith

2011). Meningeal inflammatory infiltrates reported in cortex, three distinct lesion types have been described association with subpial cortical lesions may contribute to based on the location of the plaques: subpial, intracorti- cortical inflammation and disability in some cases (Ho- cal, and leukocortical (Bogdan et al. 2013). Cortical well et al. 2011; Lucchinetti et al. 2011). lesions seen in early MS are usually highly inflammatory and correlate with cognitive impairment (Geurts and Pathology Barkhof 2008; Lucchinetti et al. 2011).

The MS plaques or lesions are focal areas of demyelina- Clinical Presentation and Diagnosis tion associated with variable inflammation and axonal loss that predominantly affect the white matter of the The clinical symptoms and signs of MS are variable and brain, spinal cord, and optic nerves but can also involve may result from involvement of sensory, motor, visual, the cerebral cortex including subpial regions (Sobel and and brainstem pathways. The majority of patients with Moore 2008; Popescu and Lucchinetti 2012). The inflam- MS initially present with relapsing remitting episodes of matory infiltrates associated with plaques consist of acti- new or recurrent neurological symptoms. The first clinical vated T cells (predominantly CD8+ with variable presence event in these patients, termed clinically isolated syn- of CD4+ cells), activated macrophages/microglia, plasma drome (CIS), can be optic neuritis, incomplete myelitis, cells, and B cells (Hauser et al. 1986; O’Connor et al. or brainstem syndrome (Miller et al. 2005). The presence 2001). MS plaques can be further classified histologically of classic demyelination lesions on baseline brain or as active, chronic, and remyelinated. Active lesions are spinal cord MRI is the most important predictor of hav- common in relapsing remitting MS and are characterized ing a second relapse in CIS patients (Filippi et al. 1994). by myelin degradation (with relative axonal preservation), The presence of cerebrospinal fluid (CSF) abnormalities macrophage infiltration, reactive astrocytes, and perivas- (positive oligoclonal bands) may have additional prognos- cular and parenchymal inflammation (Bruck et al. 1995; tic value in patients with CIS and positive brain MRI Frischer et al. 2009). Chronic or inactive plaques are (Miller et al. 2005; Awad et al. 2010). A variable propor- more often seen in patients with progressive disease and tion of patients with relapsing remitting MS (25–40%) are associated with more extensive demyelination, often develop secondary progressive disease over time with pro- with marked axonal depletion, loss of oligodendrocytes, gressive accumulation of disability with infrequent or no and relative absence of active inflammation (Prineas et al. relapses (Lublin and Reingold 1996). Primary progressive 2001; Sobel and Moore 2008; Popescu and Lucchinetti MS (seen in approximately 10–15% patients) is defined 2012). Remyelinated plaques are seen within or more by progressive accumulation of disability from the onset often at the margins of active plaques and contain thinly with no or minor relapses and typically presents with a myelinated axons and often increased numbers of oligo- progressive myelopathy with an older age of onset and dendrocyte precursor cells (Bruck et al. 1995; Popescu involving a higher proportion of men (Miller and Leary and Lucchinetti 2012). “Shadow plaques” are lesions that 2007). Both primary and secondary progressive MS share show more diffuse (but still incomplete) remyelination some clinical and imaging features and are now consid- and are seen in patients with relapsing and progressive ered to be part of the progressive disease spectrum disease (Barkhof et al. 2003). The presence of cortical (Lublin and Reingold 1996; Ingle et al. 2005; Lublin et al. demyelination and axonal loss has been increasingly rec- 2014). The progressive relapsing form of MS with wors- ognized in early MS (Trapp et al. 1998; Cifelli et al. ening disability from onset and clear acute relapses with 2002). Lucchinetti and colleagues have described four dis- or without full recovery is now considered to be progres- tinct immmopathological patterns (pattern I with macro- sive disease with disease activity (Lublin et al. 2014). phage and T-cell predominance, II with additional There is no single diagnostic test for MS and the diagno- immunoglobulin and complement deposition, III with sis is usually based on the clinical presentation, supported apoptotic oligodendrocyte loss, and the rare type IV pat- by neuroimaging and in some cases by CSF analysis (to tern with nonapoptotic death of oligodendrocytes) in look for inflammatory markers oligoclonal bands and/or active MS lesions, suggesting that there may be pathologi- elevated IgG index) and evoked potential studies (to look cal heterogeneity among MS patients (Lucchinetti et al. for clinically silent lesion in visual, brainstem, or spinal 2000). However, the observed pathologic heterogeneity cord pathways). CSF inflammatory markers are present in may not be exclusive to a subset of MS patients and is up to 85% patients with MS (Link and Huang 2006); IgG probably related to the stage of disease in a given patient index is less sensitive and specific than oligoclonal bands (Barnett and Prineas 2004). Cortical involvement can Awad et al. 2010). There have been several proposed diag- occur in MS and may reflect either the presence of corti- nostic criteria incorporating the clinical and ancillary data, cal demyelination or actual neuronal loss. Within the the most commonly used one is the McDonald criteria

Brain and Behavior, doi: 10.1002/brb3.362 (4 of 13) ª 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. N. Garg & T. W. Smith An update on Multiple Sclerosis initially proposed in 2001 and revised in 2005 and most disease and Balo’s concentric sclerosis are characterized by recently in 2011 (Polman et al. 2011). The basic concept a rapidly evolving fulminant clinical course and poor prog- behind these criteria is demonstration of dissemination in nosis. The Marburg variant has the distinct radiological fea- time (DIT) and space using the clinical and/or MRI data. ture of large tumor-like multifocal demyelinating lesions in A detailed discussion of McDonald criteria is beyond the deep white matter; the pathological changes are similar to scope of this review; in summary, the definitive diagnosis those of classicMS but may appear more destructive and of MS requires ≥2 attacks or objective clinical evidence of have more inflammatory infiltrates (Karussis 2014). The ≥ 2 lesions or objective clinical evidence of 1 lesion with pathological changes seen in Balo’s concentric sclerosis are historical evidence of a prior attack. With one clinical quite unique and consist of alternating bands of normally attack, DIT can be demonstrated by presence of asymptomatic gadolinium-enhancing and nonenhancing lesions Table 3. McDonald MRI criteria for demonstration of DIS (Polman at any time or by presence of new lesions on a follow-up et al. 2011). scan obtained anytime after the initial symptom onset or ≥ 1 the simultaneous (see Table 2). Dissemination in space DIS can be demonstrated by 1 T2 lesions in at least 2 of the 4 area of the CNS (DIS) in a patient with two clinical attacks but objective evidence of one lesion can be demonstrated by using the Periventricular MRI criteria detailed in Table 3. The criteria for primary Juxtacortical progressive MS include 1 year of disease progression plus Infratentorial 2 two of the following criteria: a. evidence of DIS in brain, b. Spinal cord ≥ DIS in spinal cord ( 2 T2 lesions in the cord), c. positive MRI, magnetic resonance imaging; DIS, lesion dissemination in space; CSF oligoclonal bands and/or elevated IgG index. CNS, central nervous system. In patients presenting with typical relapsing remitting Based on Swanton et al. 2006, 2007. symptoms and classic demyelination lesions (e.g., shown Adapted from Polman et al. (2011). 1 in Fig. 2) on neuroimaging meeting the radiological Gadolinium enhancement of lesions is not required for DIS. 2 criteria, the differential diagnosis is limited and often no If a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the Criteria and do not contribute to further diagnostic testing is indicated in these cases. lesion count. The differential diagnosis in other cases depends on the clinical presentation and is outlined in Table 4.

Atypical presentation or variants of MS There are some less common clinical variants of MS which present with atypical clinical and radiological features, these include tumefactive MS, Balo’s concentric sclerosis, and Marburg disease. The radiological hallmark of tumefactive MS is a large solitary >2 cm lesion associated with mass effect, edema and/or ring enhancement (hence the name tumefactive). The clinical symptoms depend on the size and location of the lesion and often include aphasia, agno- sia, seizures and visual ﬁeld defects, not typically seen in CIS or RRMS patients (Lucchinetti et al. 2008). Marburg’s

Table 2. McDonald MRI criteria for demonstration of DIT (Polman et al. 2011).

DIT Can be Demonstrated by

1. A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI 2. Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time Figure 2. Brain MRI axial ﬂuid attenuated inversion recovery (FLAIR) MRI, magnetic resonance imaging; DIT, lesion dissemination in time. image shows the characteristic periventricular areas of increased Based on Montalban et al. 2010. signal intensity (arrows) that are oriented perpendicular to and often Adapted from Polman et al. (2011). contiguous with the lateral ventricles.

ª 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Brain and Behavior, doi: 10.1002/brb3.362 (5 of 13) An update on Multiple Sclerosis N. Garg & T. W. Smith

Table 4. Differential diagnosis of multiple sclerosis The mechanism of action of IMT used for treatment of Optic neuritis/neuropathy MS is broad suppression of the immune response medi- Inflammatory, neuromyelitis optica (NMO) spectrum disorder, ated by autoreactive lymphocytes; most of these are effec- genetic, ischemic tive in relapsing remitting MS where inflammatory Myelitis/myelopathy— demyelination is the primary process (Weinstock-Gutt- — Inflammatory demyelination idiopathic, postviral, postvaccinialNMO man et al. 1995; Rudick et al. 1997; Damal et al. 2013). spectrum disorder, Autoimmune–systemic lupus erythematosus, The goal of these therapies is to reduce the frequency of antiphospholipid antibody syndrome, other systemic autoimmune disorders relapses and number of MRI lesions (new, enlarging and/ Infectious (Lyme disease, HIV, viral, others) or enhancing T2 lesions), and slow the disability progres- Ischemic/vascular sion. Most of these agents have shown good efficacy in Others–compressive, nutritional patients with relapsing remitting MS and clinically iso- Brainstem syndrome lated syndrome, however, their benefit in patients with € ß Stroke, tumor, vasculitis (lupus, Sjogren’s syndrome, Behcet’s progressive disease has been questionable (Filippini et al. disease) 2013). The mechanism of action and side-effect profile of Cerebral white matter lesions Small vessel disease (Leukoaraiosis) different IMTs are briefly discussed here with the excep- Migraine tion of alemtuzumab, the latest medication to be Primary CNS vasculitis approved for treatment of MS. Sarcoidosis CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) Beta-Interferon Interferons (IFNs) are endogenous proteins that are myelinated or remyelinated, and demyelinated white mat- involved in immune response against viral and bacterial ter; this pattern has been described as resembling hypoxia- agents and were the first class of disease modifying agents induced injury (Stadelmann et al. 2005). The MRI may developed for treatment of MS. The beta-interferons show alternating isointense and hypointense concentric (IFN-b) have multiple actions including stabilizing the rings with partial enhancement on T1-weighted images BBB thereby limiting the entry of T cells into the CNS, (Zettl et al. 2012; Karussis 2014). modulating T- and B-cell function, and altering the expression of cytokines (Yong et al. 1998; Weber et al. Therapeutic Options 1999; Dhib-Jalbut 2002). Several different preparations of IFN- b are available and are listed in Table 5. Both IFN- The management of MS includes treatment with immuno- b1a and IFN-b1b have shown similar efficacy and are modulatory agents that help alter the course of the disease, considered first line agents for treating patients with symptomatic management focusing on relieving specific relapsing MS and CIS (Rudick et al. 1997). Although two symptoms such as fatigue, spasticity, bladder dysfunction, different trials with IFN- b1b showed conflicting results and pain (not discussed in this review). Corticosteroids in secondary progressive MS, it may be indicated in (methylprednisolone) and adrenocorticotropic hormone patients with continued relapses (Kappos et al. 2004). (ACTH) have anti-inflammatory and immunomodulatory The side effects of beta-interferon include flu-like symp- effects and are typically used to treat acute relapse to hasten toms, depression, liver enzyme elevation, thyroid abnor- the recovery (Berkovich 2013). The immunomodulatory malities, leukopenia or anemia, and injection site therapies (IMT) used in long-term disease modification are reactions (Rudick et al. 1997). discussed in the next section. Glatiramer Acetate Immunomodulatory Therapies Glatiramer acetate (GA) or Copolymer 1 is a synthetic The most significant progress in the treatment of MS in the complex of four amino acids that mimics myelin basic last two decades has been the development of IMT. Since protein (MBP), one of the autoantigens targeted by the T the introduction of first immunomodulating medication, cells. Due to its structural similarity to MBP, GA blocks interferon beta-1b in 1993, several other medications with the formation of myelin reactive T cells and induces different mechanism of action (figure 1), mode and fre- GA-specific regulatory T-cell expression and Th2 anti- quency of administration have become available. Currently, inflammatory cytokine production (bystander suppres- there are 12 medications approved for treatment of MS, sion) (Wolinsky 1995; Rudick et al. 1997; Gran et al. including six self-injectable, three infusion based, and three 2000; Dhib-Jalbut 2002; Ruggieri et al. 2007). The clinical oral medications as listed in Table 5. efficacy of GA in terms of reducing relapse rate and MRI

Brain and Behavior, doi: 10.1002/brb3.362 (6 of 13) ª 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. N. Garg & T. W. Smith An update on Multiple Sclerosis

Table 5. Approved therapies for multiple sclerosis

Medication Dose Route Frequency Major side effects

First-line therapies Beta-interferon-1b 250 µg SC Every other day Flu-like symptoms, injection site reactions, liver (Betaseron, Bayer HealthCare enzyme elevation, thyroid abnormalities, Pharmaceuticals Inc., leukopenia or anemia, and depression Whippany, NJ) Beta-interferon-1a 30 µg IM Once a week (Avonex, Biogen Idec, Cambridge, MA ) Peginterferon beta-1a 125 µg SC Every 14 days (Plegridy, Biogen Idec, Cambridge, MA) Beta-interferon-1a (Rebif, 44 µg SC Three times weekly EMD Serono, Inc. Rockland, MA ) Beta-interferon-1b (Extavia, 250 µg SC Every other day Bayer HealthCare Pharmaceuticals Inc., Montville, NJ) Glatiramer acetate (Copaxone, 20 mg SC Daily Local injection site reactions, postinjection TEVA Neuroscience, Inc., 40 mg SC Three times weekly reaction (flushing, chest tightness, palpitation, Overland Park, KS ) and dyspnea) and rare lipoatrophy with prolonged use Second line therapies Natalizumab (Tysabri, 300 mg IV Every 4 weeks Hepatotoxicity, infusion reactions, progressive Biogen Idec, Cambridge, MA) multifocal encephalopathy (PML) Mitoxantrone (Novantrone, Weight-based dose IV Every 3 months Cardiotoxicity, secondary leukemia EMD Serono, Inc. Rockland, MA) Fingolimod (Gilenya, Novartis 0.5 mg Oral Once daily First dose bradycardia, atrioventricular block, Pharma Stein AG Stein, Switzerland) herpes virus infection, macular edema, elevated blood pressure, rare risk of PML Teriflunomide (Aubagio, Genzyme 7 and 14 mg Oral Once daily Hair loss, headache, diarrhea, hepatotoxicity, Corporation, Cambridge, MA) teratogenicity, increased risk of infections due to lymphopenia Dimethyl fumarate (Tecfidera, 240 mg Oral Twice daily GI effects-nausea, diarrhea, abdominal pain, Biogen Idec., Cambridge, MA ) flushing, pruritus, liver enzyme elevation, lymphopenia, rare cases of PML Alemtuzumab (Lemtrada, 12 mg or 24 mg IV Per day (5 days in year Serious infusion reactions, secondary Genzyme Corporation, 1, 3 days in year 2) autoimmune diseases-thryoiditis, Cambridge, MA ) thrombocytopenia, anti-glomerual basement membrane disease, increased risk of malignancies—thyroid cancer, melanoma, lymphoproliferative disorders lesions is similar to IFN-b, however, GA has somewhat interaction with VCAM-1 on endothelial cells thereby limited effect on disability progression (Rudick et al. preventing the transmigration of lymphocytes across the 1997; La Mantia et al. 2010). The side effect profile of GA BBB (Ransohoff 2007). Its superior efficacy has been is, however, more favorable and includes local injection demonstrated in two phase 3 studies with a robust effect site reactions, post injection reaction (flushing, chest on relapse rate reduction and disability progression tightness, palpitation, and dyspnea within minutes of (Miller et al. 2003; Polman et al. 2006). The major safety injection with spontaneous resolution) and rare lipoatro- concern with natalizumab is progressive multifocal leu- phy with prolonged use. koencephalopathy (PML), a serious potentially fatal opportunistic brain infection caused by reactivation of JC Natalizumab virus (Yousry et al. 2006). As of December 2014, 514 cases of PML have been reported worldwide with post- Natalizumab is a humanized monoclonal antibody that marketing use of natalizumab (TYSABRI [natalizumab] binds a4b1-integrin on lymphocytes blocking their 2014). The overall risk of PML in MS patients with

ª 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Brain and Behavior, doi: 10.1002/brb3.362 (7 of 13) An update on Multiple Sclerosis N. Garg & T. W. Smith natalizumab use is 3.78 per 1000 with a much higher risk Fingolimod is a sphingosine-1-phosphate receptor (13/1000) among patients with prolonged duration of (S1P1) modulator and was the first oral drug approved therapy (≥24 months), history of prior immunosuppres- for treatment of MS. By binding to S1P1 receptor on the sive therapy, and positive JC virus antibody status T cells, it prevents emigration of activated T cells from (Bloomgren et al. 2012; Information M, 2014). Due to lymph nodes thereby limiting their entry into the CNS the risk of PML, natalizumab now has a more limited use (Chiba et al. 1998; Pelletier and Hafler 2012). The poten- as a second line drug in patients with breakthrough dis- tial side effects of fingolimod include first dose bradycar- ease or intolerable side effects with first line therapies. dia, atrioventricular block, herpes virus infection, macular edema, elevated blood pressure, and a reported cases of Mitoxantrone PML (Cohen et al. 2010; Kappos et al. 2010; Samson 2013; Calic et al. 2015). Mitoxantrone is a synthetic anthracendione antineoplastic There have been a total of three reported cases of PML agent; its immunomodulatory effects include suppression associated with use of fingolimod, two of these occurred of T and B lymphocytes and macrophage proliferation. in context of prior immunosuppressive therapy, the third Mitoxantrone is indicated for reducing disability and most recent case, however, was reported in a patient with relapse frequency in patients with worsening relapsing no prior immunosuppressive therapy after more than remitting and secondary-progressive MS, however, its use 4 years of fingolimod use (Calic et al. 2015; Case of PML has been limited due to risk of dose-related cardiotoxicity reported in patient treated with Gilenya, 2015). A single and treatment-related leukemia (Fox 2006). case of sudden suspected cardiac death within 24 h of taking first dose of fingolimod was reported in December Oral Therapies 2011 (Lindsey et al. 2012). Even though a direct association with the medication could not be established, the US Three new oral medications have recently become avail- Food and Drug Administration and European regulatory able for treatment of relapsing MS: fingolimod, terifluno- agency released new monitoring guidelines for first dose mide, and dimethylfumarate. The efficacy of these monitoring and the drug is now contraindicated in medications has been established in several phase 3 stud- patients with history of cardiac disease or stroke and ies with comparable or somewhat better effect (compared patients on antiarrhythmic medications. to some injectable therapies) on relapse rate reduction, Teriflunomide is an active metabolite of leflunomide (a MRI lesions, and disability progression. drug used to treat rheumatoid arthritis) and is an inhibi-

Treatment algorithm for mulple sclerosis

Oﬀer IMT (IFN-β or GA) Inial clinical presentaon: or RRMS or CIS follow-up MRI (3-6 months)

CIS

Iniate ﬁrst line IMT with Diagnosis conﬁrmed by RRMS IFN-β or GA McDonald criteria

6-12 month f/u No Subopmal response Intolerable side eﬀects Further diagnosc workup to Poor compliance rule out MS mimics

Switch among ﬁrst line or to second line agents Figure 3. Treatment approach to patients with RRMS and CIS.

Brain and Behavior, doi: 10.1002/brb3.362 (8 of 13) ª 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. N. Garg & T. W. Smith An update on Multiple Sclerosis tor of enzyme dihyrdro-orotate dehydrogenase (DHODH) 2014). In response to these cases of PML, JC virus which interferes with denovo synthesis of pyrimidine in antibody testing and close monitoring for lymphopenia rapidly dividing cells (Oh and O’Connor 2013). Its anti- has been suggested in patients initiating DMF therapy inflammatory effect in MS is believed to be mediated by to improve surveillance. reducing the activity of proliferating T and B lympho- The oral medications are currently considered second cytes. Teriflunomide does not affect the resting or slowly line due to a greater risk of serious side effects making dividing hematopoietic cells which use the alternate their safety profile less favorable in patients with early DHODH independent “salvage pathway” for pyrimidine and mild disease. The main safety concern with oral med- synthesis, therefore, preserving the basic homeostatic ications is the potential for prolonged immunosuppres- functions of these cells and immune surveillance (Oh and sion increasing the risk of serious infections and also O’Connor 2013). Leflunomide is converted almost malignancies due to altered immune surveillance. A sim- entirely into teriflunomide after absorption and taken at plified treatment algorithm for patients with RRMS and the recommended doses, both drugs result in similar CIS is outlined in Figure 3. plasma concentration of teriflunomide (AUBAGIO (teri- In summary, there has been significant progress in the flunomide) Prescibing information. 2014). The short-term field of MS with better understanding of immunopatho- side effects of teriflunomide are relatively mild and include genesis, wider availability and use of MRI, and availability hair loss, headache, diarrhea, and elevated liver enzymes of disease modifying therapies. There are currently a wide (O’Connor et al. 2011). Reduction in lymphocyte and range of therapeutic options to treat MS including the neutrophil counts, elevated blood pressure, and a single recently approved oral drugs. However, balancing the case of latent tuberculosis are some of the other side safety and efficacy of these drugs remains a challenge due effects reported (O’Connor et al. 2011; Confavreux et al. to serious side effects associated with more effective thera- 2014). The potential teratogenecity of teriflunomide pies. Given the heterogeneity of MS, personalized treat- remains a major concern although several pregnancies ment by recognizing specific genetic markers in individual reported during its clinical trial did not have any adverse patients has been proposed. Also, there is an urgent need outcome. Nevertheless, strict contraception is recom- for novel therapeutic agents that can prevent or minimize mended to avoid pregnancy and a rapid elimination pro- the neuronal and/or axonal degeneration occurring in cess is undertaken in women who become pregnant while patients with progressive MS. taking teriflunomide as the drug can remain in the systems for 8 months to 2 years (Confavreux et al. 2014). Conflict of Interest Dimethylfumarate (DMF) or BG12 is the latest oral therapy to be approved for treatment of MS. Related to None declared. fumaric acid ester which has been used for treatment of psoriasis in Germany since 1990s; BG12 is as an enteric References coated formulation of DMF with improved GI tolerabil- Aichele, P., M. F. Bachmann, H. Hengartner, and R. M. ity. It is hydrolyzed to monomethyl fumarate soon after Zinkernagel. 1996. Immunopathology or organ-specific oral absorption. The mechanism of action of DMF autoimmunity as a consequence of virus infection. involves inhibition of proinflammatory pathways via Immunol. Rev. 152:21–45. activation of nuclear factor erythroid 2-related factor 2 Ascherio, A. 2013. Environmental factors in multiple sclerosis. (Nrf-2) antioxidant response pathway (Linker et al. Expert Rev. Neurother. 13:3–9. 2011). The most common side effect with DMF include Ascherio, A., and K. L. Munger. 2007a. Environmental risk nausea, diarrhea, abdominal pain which can be mini- factors for multiple sclerosis. Part I: the role of infection. mized by taking the medication with food and flushing Ann. Neurol. 61:288–299. which can be reduced by aspirin (Gold et al. 2012; Fox Ascherio, A., and K. L. Munger. 2007b. Environmental risk et al. 2014). Lymphopenia may occur although no factors for multiple sclerosis. Part II: noninfectious factors. increased infection risk was observed in phase 3 studies Ann. Neurol. 61:504–513. (Fox et al. 2012; Gold et al. 2012). There have been a few Ascherio, A., K. L. Munger, and K. C. Simon. 2010. Vitamin D cases of PML reported with use of fumaric acid ester for- and multiple sclerosis. Lancet Neurol. 9:599–612. mulations in patients with psoriasis with pronounced pro- AUBAGIO (teriflunomide) Prescibing information. 2014. longed lymphopenia being the major risk factor (Ermis Genzyme Corp. (Accessed July 23, 2014). et al. 2013; van Oosten et al. 2013; Sweetser et al. 2013). Awad, A., B. Hemmer, H. P. Hartung, B. Kieseier, J. L. There has been a recent report of a fatal case of PML Bennett, and O. Stuve. 2010. Analyses of cerebrospinal fluid in a patient with multiple sclerosis treated with in the diagnosis and monitoring of multiple sclerosis. J. – dimethyl fumarate (FDA Drug Safety Communication, Neuroimmunol. 219:1 7.

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